AP Biology 2006-2007

Genetics Notes #3Beyond Mendel’s Laws

Human Genetics

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Objectives: Understand situations that do not

follow Mendel’s laws. Incomplete dominance Co-dominance Pleiotropy Epistasis Polygenic Inheritance Sex-Linked Traits

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Extending Mendelian genetics Mendel worked with a simple system

peas are genetically simple most traits are controlled by a single gene each gene has only 2 alleles, 1 of which

is completely dominant to the other

The relationship between genotype & phenotype is rarely that simple

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Incomplete dominance Heterozygote shows an intermediate,

blended phenotype example:

RR = red flowers rr = white flowers Rr = pink flowers

make 50% less color

RR

RRWWRW

WWRW

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Incomplete dominancetrue-breeding

red flowerstrue-breeding white flowers

XP

100%

100% pink flowers

F1generation(hybrids)

self-pollinate

25%white

F2generation

25%red 1:2:1

50%pink

It’s likeflipping 2 pennies!

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Co-dominance 2 alleles affect the phenotype equally &

separately not blended phenotype human ABO blood groups 3 alleles

IA, IB, i IA & IB alleles are co-dominant

glycoprotein antigens on RBC IAIB = both antigens are produced

i allele recessive to both

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Genetics of Blood type

pheno-type

genotypeantigenon RBC

antibodiesin blood

donationstatus

A IA IA or IA itype A antigens

on surface of RBC

anti-B antibodies __

B IB IB or IB itype B antigens

on surface of RBC

anti-A antibodies __

AB IA IB

both type A & type B antigens

on surface of RBC

no antibodiesuniversal recipient

O i ino antigens on surface

of RBC

anti-A & anti-B antibodies

universal donor

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Pleiotropy Most genes are pleiotropic

one gene affects more than one phenotypic character 1 gene affects more than 1 trait dwarfism (achondroplasia) gigantism (acromegaly)

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Acromegaly: André the Giant

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Aa x aa

Inheritance pattern of Achondroplasia

a a

A

a

A a

A

a

Aa x Aa

Aa

aa aa

Aa

50% dwarf:50% normal or 1:1

AA

aa

Aa

67% dwarf:33% normal or 2:1

Aa

lethal

dominantinheritance

dwarf dwarf

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Epistasis

B_C_B_C_

bbC_bbC_

_ _cc_ _cc

How would you know thatdifference wasn’t random chance?

Chi-square test!

One gene completely masks another gene coat color in mice = 2 separate genes

C,c: pigment (C) or no pigment (c)

B,b: more pigment (black=B) or less (brown=b)

cc = albino, no matter B allele

9:3:3:1 becomes 9:3:4

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Epistasis in Labrador retrievers 2 genes: (E,e) & (B,b)

pigment (E) or no pigment (e) pigment concentration: black (B) to brown (b)

E–B–E–bbeeB–eebb

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Polygenic inheritance Some phenotypes determined by

additive effects of 2 or more genes on a single character phenotypes on a continuum human traits

skin color height weight intelligence behaviors

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Skin color: AlbinismJohnny & Edgar Winter

albinoAfricans

However albinism can be inherited as a single gene trait aa = albino

melanin = universal brown color

tyrosine melaninalbinism

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OCA1 albino Bianca Knowlton

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Sex linked traits Genes are on sex chromosomes

as opposed to autosomal chromosomes first discovered by T.H. Morgan at Columbia U. Drosophila breeding

good genetic subject prolific

2 week generations

4 pairs of chromosomes

XX=female, XY=male

1910 | 1933

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autosomal

chromosomes

sexchromosomes

Classes of chromosomes

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Huh!Sex matters?!

F2generation

100%red-eye female

50% red-eye male50% white eye male

Discovery of sex linkage

P X

F1generation(hybrids)

100%red eye offspring

true-breeding white-eye male

true-breedingred-eye female

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RR rr

What’s up with Morgan’s flies?

x

r r

R

R

Rr

Rr Rr

Rr

100% red eyes

Rr Rr

x

R r

R

r

RR

Rr rr

Rr

3 red : 1 white

Doesn’t workthat way!

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In humans & other mammals, there are 2 sex chromosomes: X & Y 2 X chromosomes

develop as a female: XX gene redundancy,

like autosomal chromosomes an X & Y chromosome

develop as a male: XY no redundancy

Genetics of Sex

X Y

X

X

XX

XY

XY

50% female : 50% maleXX

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XRXR XrY

Let’s reconsider Morgan’s flies…

x

Xr Y

XR

100% red eyes

XR

XRXr XRY

XRYXRXr

x

XRXr XRY

XR Y

XR

Xr

XRXr

XRYXRXR

XrY100% red females50% red males; 50% white males

BINGO!

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Genes on sex chromosomes Y chromosome

few genes other than SRY sex-determining region master regulator for maleness turns on genes for production of male hormones

many effects = pleiotropy!

X chromosome other genes/traits beyond sex determination

mutations: hemophilia Duchenne muscular dystrophy color-blindness

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Sex-linked usually

means“X-linked”

more than 60 diseases traced to genes on X chromosome

Duchenne muscular dystrophyBecker muscular dystrophy

Ichthyosis, X-linkedPlacental steroid sulfatase deficiencyKallmann syndromeChondrodysplasia punctata, X-linked recessive

HypophosphatemiaAicardi syndromeHypomagnesemia, X-linkedOcular albinismRetinoschisis

Adrenal hypoplasiaGlycerol kinase deficiency

Incontinentia pigmentiWiskott-Aldrich syndromeMenkes syndrome

Charcot-Marie-Tooth neuropathyChoroideremiaCleft palate, X-linkedSpastic paraplegia, X-linked, uncomplicatedDeafness with stapes fixation

PRPS-related gout

Lowe syndrome

Lesch-Nyhan syndromeHPRT-related gout

Hunter syndromeHemophilia BHemophilia AG6PD deficiency: favismDrug-sensitive anemiaChronic hemolytic anemiaManic-depressive illness, X-linkedColorblindness, (several forms)Dyskeratosis congenitaTKCR syndromeAdrenoleukodystrophyAdrenomyeloneuropathyEmery-Dreifuss muscular dystrophyDiabetes insipidus, renalMyotubular myopathy, X-linked

Androgen insensitivity

Chronic granulomatous diseaseRetinitis pigmentosa-3

Norrie diseaseRetinitis pigmentosa-2

Sideroblastic anemiaAarskog-Scott syndrome

PGK deficiency hemolytic anemia

Anhidrotic ectodermal dysplasia

AgammaglobulinemiaKennedy disease

Pelizaeus-Merzbacher diseaseAlport syndrome

Fabry disease

Albinism-deafness syndrome

Fragile-X syndrome

Immunodeficiency, X-linked,with hyper IgM

Lymphoproliferative syndrome

Ornithine transcarbamylase deficiency

Human X chromosome

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Map of Human Y chromosome?

< 30 genes on Y chromosome Sex-determining Region Y (SRY)

linked

Channel Flipping (FLP)Catching & Throwing (BLZ-1)

Self confidence (BLZ-2)note: not linked to ability gene

Devotion to sports (BUD-E)

Addiction to death &destruction movies (SAW-2)

Scratching (ITCH-E)Spitting (P2E)

Inability to express affection over phone (ME-2) Selective hearing loss (HUH)

Total lack of recall for dates (OOPS)

Air guitar (RIF)

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Hemophilia

Hh x HHXHYXHXh

XHXh

XH

Xh

XHY

Y

XH

sex-linked recessive

XH Ymale / sperm

XH

Xh

fem

ale

/ eg

gs XHXH

XHXh

XHY

XhY

XHXH XHY

XHXh XhY

carrier disease

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X-inactivation Female mammals inherit 2 X chromosomes

one X becomes inactivated during embryonic development condenses into compact object = Barr body which X becomes Barr body is random

patchwork trait = “mosaic”

XH

Xh

XHXh

patches of black

patches of orange

tricolor catscan only befemale

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Male pattern baldness Sex influenced trait

autosomal trait influenced by sex hormones age effect as well = onset after 30 years old

dominant in males & recessive in females B_ = bald in males; bb = bald in females

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Environmental effects Phenotype is controlled by

both environment & genes

Color of Hydrangea flowers is influenced by soil pH

Human skin color is influenced by both genetics & environmental conditions

Coat color in arctic fox influenced by heat sensitive alleles

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Any Questions?

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Human Genetics

1 2

3 4 5 6

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Objectives: Explain and interpret Pedigrees. Understand different patterns of

inheritance for human genetic diseases.

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Pedigree analysis Pedigree analysis reveals Mendelian

patterns in human inheritance data mapped on a family tree

= male = female = male w/ trait = female w/ trait

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Simple pedigree analysis

1 2

3 4 5 6

1 2

3 4 5 6

What’s the likely inheritance

pattern?

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Genetic counseling

Pedigree can help us understand the past & predict the future

Thousands of genetic disorders are inherited as simple recessive traits from benign conditions to deadly diseases

albinism cystic fibrosis Tay sachs sickle cell anemia PKU

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Genetic testing

sequence individual genes

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Recessive diseases The diseases are recessive because the

allele codes for either a malfunctioning protein or no protein at all Heterozygotes (Aa)

carriers

have a normal phenotype because one “normal” allele produces enough of the required protein

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Heterozygote crosses

Aa x Aa

A amale / sperm

A

a

fem

ale

/ eg

gs AA

Aa aa

Aa

Aa

A

a

Aa

A

a

AA

Aa aa

Aa

Heterozygotes as carriers of recessive alleles

carrier

carrier disease

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Cystic fibrosis (recessive) Primarily whites of

European descent strikes 1 in 2500 births

1 in 25 whites is a carrier (Aa) normal allele codes for a membrane protein

that transports Cl- across cell membrane defective or absent channels limit transport of Cl- & H2O

across cell membrane thicker & stickier mucus coats around cells mucus build-up in the pancreas, lungs, digestive tract &

causes bacterial infections without treatment children die before 5;

with treatment can live past their late 20s

normal lung tissue

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Effect on LungsChloride channeltransports salt through protein channel out of cellOsmosis: H2O follows Cl–airway

Cl–

H2O

Cl–

H2O

mucus secreting glands

bacteria & mucus build up

thickened mucus hard to secrete

normal lungs

cystic fibrosis

cells lining lungs

Cl– channel

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loss of oneamino acid

delta F508

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Tay-Sachs (recessive) Primarily Jews of eastern European (Ashkenazi)

descent & Cajuns (Louisiana) strikes 1 in 3600 births

100 times greater than incidence among non-Jews

non-functional enzyme fails to breakdown lipids in brain cells fats collect in cells destroying their function symptoms begin few months

after birth seizures, blindness &

degeneration of muscle & mental performance

child usually dies before 5yo

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Sickle cell anemia (recessive) Primarily Africans

strikes 1 out of 400 African Americans high frequency

caused by substitution of a single amino acid in hemoglobin

when oxygen levels are low, sickle-cell hemoglobin crystallizes into long rods deforms red blood cells into

sickle shape sickling creates pleiotropic

effects = cascade of other symptoms

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Sickle cell anemia Substitution of one amino acid in

polypeptide chain

hydrophilicamino acid

hydrophobic amino acid

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Sickle cell phenotype 2 alleles are codominant

both normal & mutant hemoglobins are synthesized in heterozygote (Aa)

50% cells sickle; 50% cells normal carriers usually healthy sickle-cell disease

triggered under blood oxygen stress exercise

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Heterozygote advantage Malaria

single-celled eukaryote parasite spends part of its life cycle in red blood cells

In tropical Africa, where malaria is common: homozygous dominant individuals die of malaria homozygous recessive individuals die of sickle cell

anemia heterozygote carriers are relatively free of both

reproductive advantage

High frequency of sickle cell allele in African Americans is vestige of African roots

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Prevalence of Malaria

Prevalence of SickleCell Anemia

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Huntington’s chorea (dominant) Dominant inheritance

repeated mutation on end of chromosome 4 mutation = CAG repeats glutamine amino acid repeats in protein one of 1st genes to be identified

build up of “huntingtin” protein in brain causing cell death memory loss muscle tremors, jerky movements

“chorea”

starts at age 30-50 early death

10-20 years after start

1872

Testing…Would you

want toknow?

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Genetics & culture Why do all cultures have a taboo against incest?

laws or cultural taboos forbidding marriages between close relatives are fairly universal

Fairly unlikely that 2 unrelated carriers of same rare harmful recessive allele will meet & mate but matings between close relatives increase risk

“consanguineous” (same blood) matings individuals who share a

recent common ancestor are more likely to carry same recessive alleles

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AA

Aa aa

Aa

A hidden disease reveals itself

AA x Aa

A Amale / sperm

A

a

fem

ale

/ eg

gs

Aa

AA

Aa

AA

Aa Aax

A amale / sperm

A

afe

mal

e / e

gg

s AA

Aa aa

Aa

• increase carriers in population• hidden disease is revealed

AP Biology 2006-2007

Any questions?